15-lower alkoxy pgf compounds

ABSTRACT

AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA   1,4-DI(HO-),2-(R1-OOC-V-CH2-),3-(R2-O-CH(-W)-E-)-   CYCLOPENTANE   OR A REACEMIC COMPOUND OF THAT FORMULA AND THE MIRROR IMAGE THEREOF, WHEREIN E IS -CH2-CH2-OR TRANS -CH=CH-; WHEREIN V IS EITHER -(CH2)5- OR CIS -CH=CH-(CH2)3-, PROVIDED THAT E IS -CH2CH2ONLY WHEN V IS -(CH2)5-; WHEREIN W IS 1-PENTHYL OR CIS 1-PENT-2-ENYL PROVIDED THAT W IS CIS 1-PENT-2-ENYL ONLY WHEN E IS TRANS -CH=CH- AND V IS   -CH=CH-(CH2)3-;   WHEREIN $ INDICATES ATTACHMENT TO THE CYCLOPENATANE RING IN ALPHA OR BETA CONFIGURATION; WHEREIN R1 IS HYDROGEN ALKYL OF ONE TO 8 CARBON ATOMS, INCLUSIVE OR A PHARMACOLOGICALLY ACCEPTABLE CATION, AND WHEREIN R2 IS ALKYL OF ONE TO 5 CARBON ATOMS, INCLUSIVE, WITH THE PROVISO THAT R2 IS NOT METHYL WHEB E IS TRANS -CH=CH-, V IS   -CG=CH-(CH2)5-,   W IS 1-PENTYL, AND $ IS ALPHA.

United States Patent US. Cl. 260514 D 8 Claims ABSTRACT OF THEDISCLOSURE Prost-aglandin-type compounds with an alkoxy group replacingthe hydroxyl at the C-15 position are disclosed. These are useful forthe same pharmacological purposes as the unsubstituted prostaglandins.

This is a division of application Ser. No. 140,251, filed May 4, 1971,now abandoned.

DESCRIPTION OF THE INVENTION This invention relates to compositions ofmatter, and to methods and intermediates for producing them. Inparticular, the several aspects of this invention rel-ate to novelanalogs of some of the known prostaglandins, for example, prostaglandinE (PGE prostaglandin E (PGE prostaglandin E ('PGE prostaglandin F (PGFand PGF prostagl-andin F (PGF and 'PGF prostaglandin F (PGF and PGFprostaglandin A (PGA prostaglandin A (PGA progstaglandin A '(PGAprostaglandin B (PGB prostaglandin B (PGB and prostaglandin B (PGB andthe dihydro derivatives of PGE PGF PGF PGA and PG-B to novel methods forproducing those novel prostaglandin analogs, and to novel chemicalintermediates useful in those novel methods.

Each of the above-mentioned known prost-aglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:

A systematic name for prost-anoic acid is 7-[(2}3-octyl)--cyclopent-la-ynheptanoic acid.

PGE has the following structure:

PGF, has the following structure:

PGF has the following structure:

Each of the known prostaglandins PGE PGF, PGF PGA and PGB has astructure the same as that shown for the corresponding PG, compoundexcept that in each, C-5 and C-6 are linked with -a cis carboncarbondouble bond. For example, PGE has the following structure:

Each 13,14-dihydro derivative of PGE,, PGF PGF P-GA and PG'B has astructure the same as that shown for the corresponding PG compoundexcept that in each, C-13 and C-14 are linked with a carbon-carbonsingle bond. For example, dihydro-PGE, has the following structure:

The prostaglandin formulas mentioned above each have several centers ofasymmetry. Each formula repre- "sents the particular optically activeform of the prostaglandin obtained from certain mammalian tissues,-

for example, sheep vesicular glands, swine lung, and human seminalplasam, or by reduction or dehydration of a prostaglandin so obtained.See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), andreferences cited therein. The mirror image of each formula represents amolecule of the enantiomer of that prostaglandin. The racemic form ofthe prostaglandin consists of equal numbers of two types of molecules,one represented by one of the above formulas and the other representedby the mirror image of that formula. Thus, both formulas are needed todefine a racemic prostaglandin. See Nature 212, 38 (19 66) fordiscussion of the stereochemistry of the prostaglandins. For conveniencehereinafter, use of the terms PGF PGF and the like, will mean theoptically active form of that prostaglandin with the same absoluteconfiguration as PGE obtained from mammalian tissues. When reference tothe racemic form of either of these prostaglandins is intended, the wordracemic will precede the prostaglandin name, thus, racemic PGE orracemic PGF and the like.

In the formulas given above, as well as in the formulas givenhereinafter, broken line attachments to the cyclopentane ringindicatesubstituents in alpha configuration, i.e., below the plane of thecyclopentane ring. Heavy solid line attachments to the cyclopentane ringindicate substituents in beta configuration, i.e., above the plane ofthe cyclopentane ring.

Each of the novel prostanoic acid analogs of this invention isencompassed by the following formula or by the combination of thatformula and its mirror image:

anky-000m wherein D is one of the four carboxylic moieties:

wherein E is CH CH or trans CH=CH-; wherein R 'is hydrogen, alkyl of oneto 8 carbon atoms, inclusive, or a pharmacologically acceptable action,and R is alkyl of one to carbon atoms, inclusive; wherein V is either-(CH or cis -CH=C'H-(CH provided that E is -CI-I CH only when V is -(CHwherein W is l-pentyl or cis l-pent-2-enyl provided that W is cis.1-pent-2-enyl only when E is trans CH=CH- and V is -CH'=CH-(CH andwherein indicates attachment of hydroxyl tothe cyclopentane ring inalpha or beta configuration.

Formula I, which is written in generic form for convenience, representsPG-E-type compounds when D is PGF -type compounds when D is Ho PGA-typecompounds when D is RV, Q.

and PGB-type compounds when D is Formula I represents PG -type compoundswhen E is trans --CH=CH, V is -(CH and W is l-pentyl; PG -type compoundswhen E is trans CH=CH, V is cis CH=CH'(CH and W is l-pentyl; PG typecompounds when E is trans CH=CH, V is cis CI-I =CH (CH and W isl-pent-Z-enyl; and 13,14-dihydro-PG -type compounds when E is COORI IIIO COOR VII XII

XIII

XIV

XVI

O H CODE 6 R, XVII Each of the novel prostanoic acid analogs of thisinvention has an alkoxy group at the C-15 position, i.e. the positionnormally occupied by the side-chain hydroxyl of the naturally-occurringprostaglandins. Thus, these novel prostanoic acid analogs areconveniently designated as 15-alkyl ethers of the prostaglandins, e.g.PGE l5" methyl ether, and the like.

With regard to Formulas I-XVII, examples of alkyl of one to 5 carbonatoms, inclusive, are methyl, ethyl, propyl, butyl and pentyl, andisomeric forms thereof. Examples of alkyl of one to 8 carbon atoms,inclusive, include those one to 5 carbon atom alkyl groups and, inaddition, hexyl, heptyl, and octyl, and isomeric forms thereof.

Like the natural prostaglandins described above, these novel 15-alky1ethers prostaglandin compounds have several centers of asymmetry. As inthe case of the formulas representing the prostaglandins, Formulas Ithrough XVII, inclusive, are intended to represent optically activeprostanoic acid analogs with the same configuration as PGE obtained frommammalian tissues. The novel prostanoic acid derivatives of thisinvention also include the corresponding racemic compounds. For example,Formula II and its mirror image are necessary in combination to describethe racemic PGE compounds. For convenience hereinafter, when the wordracemic precedes the name of one of the novel prostanoic acidderivatives of this invention, the intent is to designate a racemiccompound represented by the combination of the appropriate Formula Ithrough XVII and the mirror image of the formula. When the word racemicdoes not precede the compound name, the intent is to designate anoptically active compound represented only by the appropriate Formula (Ithrough XVH and with the same absolute configuration as PGE obtainedfrom animal tissues.

PGE PGE PGE and dihydro-PGE and the corresponding PGF,,, PGF,,, PGA, andPGB compounds, and their esters and pharmacologically acceptable salts,are extremely potent in causing various biological responses. For thatreason, these compounds are useful for pharmacological purposes. See,for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), andreferences cited therein. A few of those biological responses aresystemic arterial blood pressure lowering in the case of the PGE andPGF, compounds as measured, for example, in anesthetized (penobarbitalsodium) pentoliniumtreated rats with indwelling aortic and right heartcannulas; pressor activity, similarly measured, for the PGF, compounds;stimulation of smooth muscle as shown, for example, by tests on stripsof guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation ofother smooth muscle stimulants; antilipolytic activity as shown byantagonsim of epinephrine-induced mobilization of free fatty acids orinhibition of the spontaneous release of glycerol from isolated rat fatpads; inhibition of gastric secretion in the case of the PGE and PGAcompounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; decrease ofblood platelet adhesiveness as shown by platelet-toglass adhesiveness,and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE and PGB compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdisease and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 g. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 g. to about 500 g.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about mg. per kg. of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

The PGE, PGF, and PGF, compounds are useful whenever desired to inhibitplatelet aggregation, to reduce the adhesive character of platelets, andto remove or prevent the formation of thrombi in mammals, including man,rabbits, and rats. For evample, these compounds are useful in treatmentand prevention of myocardial infarcts, to treat and preventpost-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atheroschlerosis,arterioscleorosis, blood clotting defects due to lipemia, and otherclinical conditions in Which the underlying etiology is associated withlipid imbalance or hyperlipidemia. For these purposes, these compoundsare administered systemically, e.g. intravenously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred. Doses in the range ofabout 0.005 to about 20 mg. per kg. of body Weight per day are used, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration.

The PGE, PGF and PGF, compounds are especially useful as additives toblood, blood products, blood substitutes, and other fluids which areused in artificial extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation ap paratus. This blocking is avoided by the presence ofthese compounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to tWo or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore PGE for example, is useful in place of or in combination withless than usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atomic uterine bleeding after abortion ordelivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 g. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during pucrperiumin the range of 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PG-E and PGF, compounds are useful as hypotensive agents to reduceblood pressure in mammals including man. For this purpose, the compoundsare administered by intravenous infusion at the rate about 0.01 to about50 g. per kg. of body weight per minute, or in a single or multipledoses of about 25 to 500 g. per kg. of body weight total per day.

The PGE, PGF,, and PGE compounds are useful in place of oxytocin toinduce labor in pregnant female animals, including man, cows, sheep,pigs, at or near term, or in pregnant animals with intrauterine death ofthe fetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose 0.01 to 50' g. per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks postmature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started.

The IPGE, PGE,, and PGF, compounds are useful for controlling thereproductive cycle in ovulating female mammals, including humans andother animals. For that purpose, PGF for example, is administeredsystematically at a dose level in the range 0.01 mg. to about 20 mg. perkg. of body weight, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod. Because the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids, they are useful inexperimental medicine for both in vitro and in vivo studies in mammals,including man, rabbits, and rats, intended to lead to the understanding,prevention, symptom alleviation, and cure of diseases involving abnormallipid mobilization and high free fatty acid levels, e.g., diabetes,mellitus, vascular diseases, and hyperthyroidism.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimpaired renal blood flow, for example, the hepatorenal syndrome andearly kidney transplant rejection. In cases of excessive orinappropriate ADH (antidiuretic hormone; vasopressin) secretion, thediuretic effect of these compounds is even greater. In anephreticstates, the vasopressin action of these compounds is especially useful.Illustrativey, the PGA compounds are useful to alleviate and correctcases of edema resuting, for example, from The PGE and PGB compoundspromote and accelerate the growth of epidermal cells and keratin inanimals, including humans, and other animals. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These compounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressing, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The eifect dose depends on such factors as the routeof administration, and the age, weight, and conditions of the subject.To illustrate, a wet dressing for topical application to second and/orthird degree burns of skin area to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 ,ug./ml. of the PGB compound or several times that concentrationof the PGE compound. Especially for topical use, these prostaglandinsare useful in combination with antibiotics, for example, gentamycin,neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example, hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The novel Formula ll-to-V PGB-type compounds, the novel Formula VI-to-IXPGF,-type and PGF,-type compounds, the novel Formula X-to-XIII PGA-typecompounds, and the novel Formula XIV-to-XVII PGB-type compounds eachcause the biological responses described above for the PGE, PGF PGF,,,PGA, and PGB compounds, respectively, and each of these novel compoundsis accordingly useful for the above-described corresponding purposes,and is used for those purposes in the same manner as described above.

The known PGE, PGF,, PGF,, PGA, and PGB compounds are all potent incausing multiple biological responses even at low doses. For example,PGE and PGE are extremely potent in causing vasodepression and smoothmuscle stimulation, and also are potent as antilipolytic agents.Moreover, for many applications, these known prostaglandins have aninconveniently short duration of biological activity. In strikingcontrast, the novel prostaglandin analogs of Formulas II to XVII aresubstantially more specific with regard to potency in causingprostaglandin-like biological responses, and have a substantially longerduration of biological activity. Therefore, each of these novelprostaglandin analogs is surprisingly and unexpectedly more useful thanone of the corresponding above-mentioned known prostaglandins for atleast one of the pharmacological purposes indicated above for thelatter, because it has a different and narrower spectrum of biologicalactivity than the known prostaglandins, and therefore is more specificin its activity and causes smaller and fewer undesired side effects thanthe known prostaglandins. Moreover, because of its prolonged activity,fewer and smaller doses of the novel prostaglandin analog can frequentlybe used to attain the desired result.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively orally, sublingually, intravaginally, buccally,or rectally, in addition to the usual intravenous, intramuscular, orsubcutaneous injection or infusion methods indicated above for the usesof the known prostaglandins. These qualities are advantageous becausethey facilitate maintaining uniform levels of these compounds in thebody with fewer, shorter, or smaller doses, and make possibleself-administration by the patient.

The 15-alkyl ether PGE, PGF,, PGF,, PGA, and PGB type compoundsencompassed by Formulas II through XVII above are used for the purposesdescribed above in the free acid form, in ester form, or inpharmacologically acceptable salt form. When the ester form is used, theester is any of those within the above definition of R However, it ispreferred that the ester be alkyl of one to four carbon atoms,inclusive. Of those alkyl, methyl, and ethyl are especially preferredfor optimum absorption of the compound by the body or experimentalanimal system.

Pharmacologically acceptable salts of these Formula II-to-XVII compoundsuseful for the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylarnine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,Z-methylpyrrolidine, 1,4-dimethylpiperazine, Z-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethylidethanolamine,N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-l,3-propanediol, 2 amino-Z-methyl-l-propanol,tris(hydroxymethyl)aminomethane, N phenylethanolamine,N-(p-tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine,N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine,and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylanunonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of Formulas H through XVII areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. 1

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred because ofincreased water solubility that R in the Formula II-to-XVII compound behydrogen or a pharmacologically acceptable cation. For subcutaneous orintramuscular injection, sterile solutions or suspensions of the acid,salt, or ester form in aqueous or non-aqueous media are used. Tablets,capsules, and liquid preparations such as syrups, eliXirs, and simplesolutions, with the usual pharmaceutical carriers are used for oral orsublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, asterile tablet or silicone rubber capsule or other object containing orimpregnated with the substance is used.

The 15-alkyl ether prostaglandin-type compounds encompassed by FormulasI through XVII inclusive, are produced by the reactions and proceduresdescribed and exemplified hereinafter.

CHART A CHART B l? O XXVI THP o o R,

XXVII (b)/ H0 A, (c) THPo on,

XXVIII W, \/\/\A/\/ Taro on,

XXIX (d)/ Taro on,

XXX

i 000E W Ho 6R,

XXXI Referring to Charts A and B, the 15-a1kyl ether PGE compounds ofFormula XXXI are produced from alkyl ether intermediates of FormulaXXVI. Therein, and throughout this disclosure, R is alkyl of one to 5carbon atoms, inclusive, the most preferred forms of alkyl being methyland ethyl. The Formula XXVI intermediates are prepared by the sequenceof steps shown in Chart A, using intermediates XIX through XXV wherein Ris either benzoyl or acetyl. Generally for ease in pruification, and foreconomies and higher yields, benzoyl is preferred.

In Charts A and B, as in subsequent Charts herein, the formulas asdepicted represent optically active compounds.

The same sequence of steps is applicable to the racemic compoundsconsisting of the optically active compounds as depicted and the mirrorimages thereof, thereby yielding the racemic intermediates and thencethe racemic PG products.

Previously, the preparation of an intermediate bicyclic lactone diol ofthe formula was reported by E. I. Corey et al., J. Am. Chem. Soc. 91,5675 (1969), and later disclosed in an optically active form by E. J.Corey et al., I. Am. Chem. Soc. 92, 397 (1970). Conversion of thisintermediate to PGE and PGF either in racemic or optically active form,was disclosed in those publications. Conversion to P-GE and PGF wasdisclosed by Corey et al., J. Am. Chem. Soc. 93, 1490 (1971).

The iodolactone of Formula XVIII in Chart A is known in the art (seeCorey et al., above). It is available in either racemic or opticallyactive or form. For racemic products, the racemic form is used. Forprostaglandins of natural configuration, the levorotatory form is used.

The Formula XIX compound bears an R O- moiety at the 4-position, whereinR is as defined above. In preparing the Formula XIX compound byreplacing the hydrogen of the hydroxyl group in the 4-position with theacyl group R methods known in the art are used. Thus, if R is benzoyl,benzoic acid is reacted with the Formula XVIII compound in the presenceof a dehydrating agent, e.g. sulfuric acid, zinc chloride, or phosporylchloride; or benzoic anhydride is used.

\Preferably, however, an acyl halide, for example benzoyl chloride oracetyl chloride, is reacted with the Formula XVIII compound in thepresence of a hydrogen chloride-scavenger, e.g. a tertiary amine such aspyridine, triethylamine, and the like. The reaction is carried out undera variety of conditions using procedures generally known in theart.Generally, mild conditions are employed, e.g. 20-60 C., contacting thereactants in a liquid medium, e.g. excess pyridine or an inert solventsuch as benzene, toluene or chloroform. The acylating agent is usedeithergin stoichiometric amount or in excess.

The Formula XX compound is next obtained by deiodination of XIX using areagent which does not react with the lactone ring or the OR;, moiety,e.g. zinc dust, sodium hydride, hydrazine-palladium, hydrogen and Raneynickel or platinum, and the like. Especially preferred is tributyltinhydride in benzene at about 25 C. with2,2'-az0*bis-(2-methylpropionitrile) as initiator.

The Formula XXI compound is obtained by demethylation of XX with areagent that does not attack the R moiety, for example boron tribromideor trichloride. The reaction is carried out preferably in an inertsolvent at about 0-5 C.

The Formula XXII compound is obtained by oxidation of the -CH OH of XXIto CHO, avoiding decomposition of the lactone ring. Useful for thispurpose are dichromate-sulfuric acid, Jones reagent, lead tetraacetate,and the like. Especially preferred is Collins reagent (pyridine-CrO atabout 0-10 C.

The Formula XXIII compound is obtained by Wittig alkylation of XXII,using the sodio derivative of dimethyl 2-oxoheptylphosphonate. The transenone lactone is obtained stereospecifically (see D. H. Wadsworth etal., J. Org. Chem., Vol. 30, p. 680 (1965)).

The Formula XXIV compound is obtained by reduction of XXIII, yielding amixture of alpha and beta isomers. For this reduction, use is made ofany of the known ketonic carbonyl reducing agents which do not reduceester or acid groups or carbon-carbon double bonds when the latter isundesirable. Examples of those are the metal borohydrides, especiallysodium, potassium, and zinc borohydrides, lithium(tri-tert-butoxy)aluminum hydride, metal trialkoxy borohydrides, e.g.,sodium trimethoxyborohydride, lithium borohydride, diisobutyl aluminumhydride, and when carbon-carbon double bond reduction is not a problem,the boranes, e.g., disian lylborane.

For production of natural-configuration PG-type analogs, the desiredalpha form of the Formula XXIV compound is separated from the betaisomer by silica gel chromatography.

The Formula XXV compound is prepared by alkylation of the side-chainhydroxy of the Formula XXIV compound thereby replacing hydroxy with the-OR moiety. For this purpose, diazoalkanes may be employed, preferablyin the presence of a Lewis acid, e.g. boron trifiuoride etherate,aluminum chloride, or fiuoboric acid. When R is methyl, diazomethane isused. See Fieser et al., Reagents for Organic Synthesis, John Wiley andSons, Inc., N.Y. (1967), p. 191. Other -OR groups are formed by usingthe corresponding diazoalkane. For example diazoethane and diazobutaneyield -OC H and -OC H respectively. The reaction is carried out bymixing a solution of the diazoalkane in a suitable inert solvent,preferably ethyl ether, with the Formula XXIV compound. Generally thereaction proceeds at about 25 C. Diazoalkanes are known in the art orcan be prepared by methods known in the art. See, for example, OrganicReactions, John Wiley and Sons, Inc., N.Y., Vol. 8, pp. 389-394 (1954).

Another method for the alkylation of the side chain hydroxy is by thereaction of an alcohol in the presence of boron trifiuoride etherate.Thus, methanol and boron trifluoride etherate yield the methyl etherwherein R is methyl. The reaction is done at about 25 C. and isconveniently followed with thin layer chromatography (TLC).

Another method for the alkylation of the side-chain hydroxy is by thereaction of an alkyl halide, e.g. methyl iodide, in the presence of ametal oxide or hydroxide, e.g. barium oxide, silver oxide, or bariumhydroxide. An inert solvent may be beneficial, for example benzene ordimcthylformamide. The reactants are preferably stirred together andmaintained at temperatures of 2575 C.

Still another method is by first converting the hydroxy to mesyloxy(i.e. methanesulfonate) or tosyloxy (i.e. toluenesulfonate) and thencetransforming the mesyloxy or tosyloxy to the OR moiety by reaction witha metal alkoxide, e.g. potassium tert-butoxide. The mesylate or tosylateis prepared by reaction of the Formula XXIV intermediate with eithermethanesulfonyl chloride or toluenesulfonyl chloride in pyridine.Thereafter, the mesylate or tosylate is mixed with the appropriatepotassium or sodium alkoxide in pyridine, the reaction proceedingsmoothly at about 25 C. An equivalent amount of the alkoxide based onthe mesylate is preferred to avoid side reactions. In this manner, theFormula XXV intermediate is prepared wherein R is normal alkyl,secondary alkyl, or tertiary alkyl of one to 5 carbon atoms. The methodis especially useful for tertiary alkyl substitutions for hydrogen, e.g.where R is tert-butyl or tert-pentyl.

The Formula XXVI compound is then obtained by deacylation of XXV with analkali metal carbonate, for example potassium carbonate in methanol atabout 25 C.

The process for producing a compound of the formula mo 6H wherein R isas defined above, replacing the hydroxy with the OR moiety, andthereafter replacing the OR moiety with hydroxy.

The transformations of the Formula XXVI compounds to the Formula XXXIPGE -type compounds are shown in Chart B. The Formula XXXI products fallwithin the scope of Formula III.

In step a, the tetrahydropyranyl ether XXVII is obtained by replacingthe ring hydroxyl with tetrahydropyranyloxy. To accomplish this, theFormula XXVI compound is reacted with dihydropyran in an inert solvent,e.g. dichloromethane, in the presence of an acid condensing agent suchas p-toluenesulfonic acid. The dihydropyran is used in excess,preferably 4 to times theory. The reaction is normally complete in -30min. at 30 C.

In step b, the lactol XXVIII is obtained on reduction of the 0x0 of theFormula XXVII lactone without reducing the 13,14-et-hylenic group. Forthis purpose, diisobutylaluminum hydride is preferred. The reduction ispreferably done at 60 to 70 C.

In step c, the Formula XXIX compound is obtained by a Wittig alkylation,using a Wittig reagent derived from 4-carboxybutyl triphenylphosphoniumbromide, and sodio dimethylsulfinylcarbanide. The Wittig reagent isprepared from an intermediate Hal-(CH COOH compound wherein Hal ischloro or bromo by methods known in the art. See, for example, Fieser etal., op. cit. pp. 1238-1242. The reaction with the Formula XXVIII lactoloccurs readily at about C. This Formula XXIX compound serves as anintermediate for preparing either the PGE -type or the PGF -typeproducts, Charts B and C respectively.

To prepare the Formula XXXI (III) PGE -type compounds, the Formula XXIXtetrahydropyranyl ether is oxidized at the 9-hydroxy position,preferably with Jones reagent, to form 9-oxo, step d. Finally, in stepe, the tetrahydropyranyl groups are replaced with hydrogen, byhydrolysis, e.g. with methanol/HCl or with acetic acid/water/tetrahydrofuran at 4055 C. thereby avoiding formation of PGA -typecompounds as by-products.

There is therefore provided a process for producing a PGE -type compoundof the formula XX XI wherein R is as defined above, which comprisesstarting with a reactant of the formula XXVI , a and subjecting itsuccessively to the steps of (a) replacement of free ring hydroxyl withtetrahydropyranyloxy;

(b) reduction of the lactone 0x0 to hydroxy;

(c) Wittig alkylation with a compound of the formula Hal(CH COOH whereinHal is bromo or chloro;

(d) oxidation of 9-hydroxy to oxo; and

(e) transformation of tetrahydropyranyloxy to hydroxy.

In like manner the racemic product consisting of the Formula XXXIcompound and its mirror image is produced by starting with a racemicreactant consisting of the Formula XXVI compound and its mirror image.

CHART 0 In Chart C are shown the transformations of the Formula XXVIcompounds to PGF -type compounds of Formula XXXII, which are Within thescope of Formula VII when is alpha.

The Formula XXVI starting material is transformed to the Formula XXIXintermediate by the steps described above and illustrated in Chart B,steps a through c. The tetrahydropyranyloxy group of the Formula XXIXcompound is then replaced with hydroxy by hydrolysis, e.g. withmethanol/HCl or with acetic acid/water/tetrahydrofuran at 40-55 C. toyield the Formula XXXII products.

17 There is therefore provided a process for producing a PGE,-typecompound of the formula Ho 6 R1 xxxrr wherein R is as defined abovewhich comprises starting with a reactant of the formula and subjectingit successively to the steps of XXVI In like manner, the racemic productconsisting of the Formula XXXII compound and its mirror image isproduced by starting with a racemic reactant consisting of the FormulaXXVI compound and its mirror image.

CHART D In Chart D is shown a general method for preparing the FormulaXXXIV alkyl ester lS-alkyl ether compounds and thence the Formula XXXVfree acid 15-alkyl ether 0 compounds useful per se or for preparingesters or salts.

The reactant compounds encompassed by Formula XXXIII of Chart D are thefree acids and alkyl esters of the P6 compounds of PGE, PGE,, PGF, PGAand PGB, and also the corresponding PG P6 and 13,14-di- 5 hydro-PGcompounds. In generic Formula XXXIII, the symbols D, E, R V, and W areas defined above.

The initial optically active reactants of Formula XXXIII in Chart D areknown in the art or are prepared by methods known in the art. See, forexample, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968); US. Pat. No.3,069,322; British Specification No. 1,040,544; Corey et al., J. Am.Chem. Soc. 92, 397 (1970), 92, 2586 (1970), and 93, 1490 (1971). Theinitial racemic reactants of Formula XXXIII in Chart D are known in theart or are prepared by methods known in the art. See for example, Justet al., I. Am. Chem. Soc. 91, 5364, (1969), Corey et al., J. Am. Chem.Soc. 90, 3245 (1968), and 91, 5675 (1969), Schneider et al., Chem.Commun. (Great Britain), 304, (1969), and Axen et al., Chem. Commun.(Great Britain), 602 (1970).

In step f of Chart D the various PGE and PGF compounds encompassed byFormula XXXIII and its mirror image are subjected to monoalkylation sothat the C-l5 hydroxyls are thereby converted to C-lS alkyl ether groupswithin the scope of this invention, i.e. OR moieties wherein R, is asdefined above. For this purpose, the methods discussed above inalkylating the Formula XXIV compounds to replace OH with OR are useful.Thus, either (a) diazoalkanes, e.g. diazomethane, (2) alkyl halides,e.g. methyl iodide, ethyl chloride, and the like, with silver oxide or(3) metal alkoxides are employed. The conditions are generally the sameas those used for forming the OR moiety on the Formula XXV compounds ofChart A, discussed above, except that the reactions are controlled tominimize the formation of impurities and by-products. The duration ofthe reaction for various reaction conditions, e.g. temperature,concentration, agitation, presence of catalysts, and the like, isoptimized for the C-15 alkyl ether simply by following the course of thereaction by thin layer chromatography (TLC) and observing the productionof that C-15 ether in comparison with the formation of undesiredby-prodnets and impurities. The monohydroxy PGA and PGB compounds arenot as likely to yield by-products.

The desired l5-alkyl ethers are separated from the reaction mixtureimpurities and unreacted starting material by methods known in the art,for example silica gel chromatography, including thin layer and columnchromatography, and countercurrent distribution procedures. See Ramwelland Daniels, Chromatography of the Prostaglandins, in LipidChromatographic Analysis, Vol. 2, G. V. Marinetti, ed., Marcel Dekker,Inc., N.Y., 1969.

Generally the free carboxyl groups of the Formula XXXIII reactants wherein R is hydrogen are also esterified in this process, so that thecorresponding alkyl esters are produced rather than the free acid. InFormula XXXIV, R is alkyl of one to 8 carbon atoms, inclusive. In stepg, the formula XXXV free acid alkyl ethers are formed from the FormulaXXXIV esters of several methods. For the PGF and PGB compounds,saponification may be employed, e.g. with sodium or potassium hydroxide,using methods known in the art. For the PGE and PGA compounds, which aresensitive to the normally alkaline conditions used for saponification,other methods known in the art for converting esters to acids arerequired. Especially preferred is enzymatic hydrolysis, discussed inmore detail below.

There as therefore provided a process for producing a compound of theformula wherein D, E, R R V, and W are as defined above, which comprisesstarting with a reactant of the formula wherein D, E, R V, and W are asdefined above, replacing the side-chain hydroxy with the OR moietywherein R is as defined above, and separating the alkyl ether productcompound from the reaction mixture.

In like manner, the racemic product consisting of the Formula XXXIVcompound and its mirror image is produced by starting with a racemicreactant consisting of the Formula XXXIII compound and its mirror image.

In addition to the methods described above, reference to Chart E willshow other useful methods.

CHART E GHVGOOR4 E-( 3HW 1 HO XXXVII I carbonyl reduction --OH;VCOORacid --CH:- C

E-CH-W E( JHW I (B: 63: HO

XXXVI XXXVIII base base l CHr-VCOORa E-CH-W 6R! XXXIX The various PGF-type and PGF -type compounds encompassed by Formulas VI to IX (XXXVII,Chart E) are prepared by carbonyl reduction of the correspondingPGB-type compounds (XXXVI, Chart E). For example, carbonyl reduction ofPGE 15-methyl ether, gives a mixture of PGF IS-methyl ether, and PGF15-methyl ether.

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example, Bergstrom et al., Arkiv Kemi 19,' 563 (1963), Acta.Chem. Scand. 16, 969 (1962), and British Specification No. 1,097,533.Any reducing agent is used which does not react with carbon-carbondouble bonds or ester groups. Preferred reagents are lithium(tri-tert-butoxy) aluminum hydride, the metal borohydrides, especiallysodium, potassium and zinc borohydrides, and the metal trialkoxyborohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alphaand beta hydroxy reduction products are separated into the individualalpha and beta isomers by methods known in the art for the separation ofanalogous pairs of known isomeric prostanoic acid derivatives. See, forexample, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem.240, 457 (1965), and Green et al., J. Lipid Research 5, 117 (1964).Especially preferred as separation methods are partition chromatographicprocedures, both normal and reversed phase, preparative thin layerchromatography, and countercurrent distribution procedures.

The various PGA-type compounds encompassed by Formulas X to XIII(XXXVIII, Chart E) are prepared by acidic dehydration of thecorresponding PG E-type compounds. For example, acidic dehydration ofPGE 15- ethyl ether gives PGA 15-ethyl ether.

These acidic dehydrations are carried out by methods known in the artfor acidic dehydrations of known prostanoic acid derivatives. See, forexample, Pike et al., Proc. Nobel Symposium II, Stockholm (1966),Interscience Publishers, New York, pp. 162-163 (19 67); and BritishSpecification 1,097,533. Alkanoic acids of 2 to 6 carbon atoms,inclusive, especially acetic acid, are preferred acids for this acidicdehydration. Dilute aqueous solutions of mineral acids, e.g.,hydrochloric acid, especially in the presence of a solubilizing diluent,e.g., tetrahydrofuran, are also useful as reagents for this acidicdehydration, although these reagents may cause partial hydrolysis of anester reactant.

The various PGB-type compounds encompassed by Formulas XIV to XVII(XXXIX, Chart E) are prepared by basic dehydration of the correspondingPGB-type compounds, or by contacting the corresponding PGA-typecompounds with base. For example, both PGE 15-methyl ether and PGAIS-methyl ether give PGB 15-methyl ether, on treatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555 (1963). The base is any whose aqueous solution has pH greater than10. Preferred bases are the alkali metal hydroxides. A mixture of waterand suflicient of a water-miscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The PGE-type orPGA-type compound is maintained in such a reaction medium until nofurther PGB-type compound is formed, as shown by the characteristicultraviolet light absorption near 278 m for the PGB-type compound.

In Chart E, the various symbols, E, R R,,, V, W, and have the samemeaning ascribed to them above. The reaction steps shown for thecompounds in Chart E are also applicable to the racemic compoundsconsisting of the optically active compounds as depicted and the mirrorimages thereof, thereby yielding the racemic PGF, PGA, and PGB products.

CHART F (5 R: O XXXVI In Chart F is shown a preferred methods fortransforming PGE compounds to PGF compounds, and especially PGF,compounds. Therein, Formulas XXXVI to XLII represent optically activecompounds, and E, R R.,,, V, W, and are as defined above; R is eitheralkyl of one to 8 carbon atoms, inclusive, or (A) Siwherein A is alkylof one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with oneor 2 fiuoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, oraralkyl of 7 to 12 carbon atoms, inclusive; and R is either hydrogen or(A) -Jias defined above. The same sequence of steps is applicable to theracemic compounds consisting of the optically active compounds as shownand the mirror images thereof.

The various PGF-type 15-a1kyl ether compounds encompassed by FormulaXLII are prepared by carbonyl reduction of the Formula XXXVI PGE-type15-alkyl ether compounds or their alkyl esters. Although the FormulaXXXVI compounds, and their racemic compounds with mirror images thereof,may be reduced directly to the corresponding Formula XXXVII compounds,it may be preferred for a high ratio of the PGF -type compounds over theco-formed PG-F, compounds to transform the ll-hydroxy groups to (A)-Si--O- moieties, as defined above, by silylation prior to the reductionstep. The various As of a Si-(A) moiety are alike or different. Forexample, -Si-(A) can be trimethylsilyl, dimethylphenylsilyl, ormethylphenylbenzylsilyl.

Referring to Chart F, the Formulas XL and XLI compounds may be (I)esters, i.e. where R of the Formula XXXVI compound is alkyl, R is alsoalkyl; (2) acids, i.e. derived from acid-form Formula XXXVI compoundswithout silylation, whereby R is hydrogen; or (3) silylated, whereby Ris (A) -Si as above defined. If, as is preferred, the Formula XXXVIcompounds are subjected to silylation prior to reduction, R is (A) -Si-;if not silylated, R is hydrogen.

Silylation is accomplished by procedures known in the art. See, forexample, Pierce, Silylation of Organic Compounds, Pierce Chemical Co.,Rockford, Ill. (1968). Sufficient silylating agent is used to transformthe ll-hydroxy groups to (A) -SiO moieties. As to the silylating agentsknown in the art, see, for example, Post, Silicones and Other OrganicSilicon Compounds, Reinhold Publishing Corp., New York, N.Y. (1949).

When the acid-form Formula XXXVI compounds are used, excess silylatingagent and prolonged treatment also transforms the COOH to COO-SI(A) Itis optional whether or not the COOH of the Formula XXXVI reactants isesterified to COOSi-(A) Referring again to Chart F, step i, in thepreferred process the monoor disilylated Formula XL PGE-typeintermediates are reduced to the corresponding silylated Formula XLIPGF-type compounds. These ring carbonyl reductions are carried out bymethods known in the art, as discussed above in connection with Chart E.

Following the reduction, the silylated Formula XLI PGF-typeintermediates are hydrolyzed, in step i, to the corresponding FormulaXXXVH compounds wherein R and R silyl groups are replaced with hydrogen.These hydrolyses are carried out by prior art procedures known to beuseful for transforming silyl ethers and silyl esters to alcohols andcarboxylic acids, respectively. See, for example, Pierce, cited above,especially p. 447 thereof. A mixture of water and sufficient of awater-miscible organic diluent to give a homogeneous hydrolysis reactionmixture represents a suitable reaction medium. Addition of a catalyticamount of an organic or inorganic acid hastens the hydrolysis. Thelength of time required for the hydrolysis is determined in part by thehydrolysis temperature. With a mixture of water and methanol at 25 C.,several hours is usually sufiicient for hydrolysis. At 0 C., severaldays is usually necessary.

The mixtures of PGF-type alpha and beta hydroxy reduction products areseparated into the individual Formula XXXVII alpha and beta isomers bymethods known in the art.

Finally in step k of Chart F, the PGF-type esters of Formula XXXVII arehydrolyzed or saporn'fied to the Formula XLII free acids by the usualknown procedures, as discussed above.

The PGF-type acids provide a route for the preparation of PGB-typeacids.

The PGB-type l5-alkyk1 ether free acids are obtained on oxidation of thecorresponding UGF-type l5-alkyl ethers free acid compounds. Oxidationreagents useful for this transformation are known to the art. Anespecially useful reagent for this purpose is the Jones reagent, i.e.,acidified chromic acid. See J. Chem. Soc. 39 (1946). Acetone is asuitable diluent for this purpose, and a slight excess beyond the amountnecessary to oxidize one of the secondary hydroxy groups of the PGFreactant is used. Reaction temperatures at least as low as about 0 C.should be used. Preferred reaction temperatures are in the range 10 to50 C. The oxidation proceeds rapidly and is usually complete in about 5to 20 minutes. The excess oxidant is destroyed, for example by additionof a lower alkanol, advantageously, isopropyl alcohol, and the PGE-type15-alkyl ether product is isolated by conventional methods.

Examples of other oxidation reagents useful for this transformation aresilver carbonate on Celite (Chem. Commun. 1102 (1969)), mixtures ofchromium trioxide and pyridine (Tetrahedron Letters 3363 (1968), J. Am.Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351 (1962)), mixturesof sulfur trioxide in pyridine and dimethyl sulfoxide (J. Am. Chem. Cos.89, 5505 (1967)), and mixtures of dicyclohexyl-carbodiimide and dimethylsulfoxide (J. Am. Chem. Soc. 87, 5661 (1965)).

The various l3,l4-dihydro-PGE -type, -PGF ,,-type, -PGF ,,-type, -PGA-type and -PGB -type 15-alkyl ether compounds encompassed by Formulas V,IX, XIH, and XVII are prepared by carbon-carbon double bond reduction ofthe corresponding PGE PGF PGF PGA and PGB -type compound containing atrans 13,14-double bond in the hydroxy-containing side chain. A cis ortrans double bond can also be present in the carboxy-terminated sidechain of the unsaturated reactant, as in PG -type compounds and will bereduced at the same time to --CI-I CH- Likewise, a 17,18- double bond inthe PG;- type compounds will be reduced to the CH CH moiety.

These reductions are carried out by reacting the unsaturated PGE, PGFPGF PGA, or PGB type 15-alkyl ether compound with diimide, following thegeneral procedure described by van Tamelen et al., J. Am. Chem. Soc. 83,3725 (1961). See also Fieser et al., Topics in Organic Chemistry,Reinhold Publishing Corp., New York, pp. 432-434 (1963) and referencescited therein. The unsaturated acid or ester reactant is mixed with asalt of azodiformic acid, preferably an alkali metal salt such as thedisodium or dipotassium salt, in the presence of an inert diluent,preferably a lower alkanol such as methanol or ethanol, and preferablyin the absence of substantial amounts of water. At least one molecularequivalent of the azodiformic acid salt is used for each multiple bondequivalent of the unsaturated reactant. The resulting suspension is thenstirred, preferably with exclusion of oxygen, and the mixture is madeacid, advantageously with a carboxylic acid such as acetic acid. When areactant wherein R is hydrogen is used, the carboxylic acid reactantalso serves to acidify an equivalent amount of the azodiformic acidsalt. A reaction temperature in the range of about to about 40 C. isusually suitable. Within that temperature range, the reaction is usuallycomplete within less than 24 hours. The desired dihydro product is thenisolated by conventional methods, for example, evaporation of thediluent, followed by separation from inorganic materials by solventextraction.

In the case of the unsaturated PGE, PGF and PGB,- type reactants, thereductions to the corresponding 13,14- dihydro-PGE dihydro-PGF anddihydro-PGF -type compounds are also carried out by catalytichydrogenation. For that purpose, palladium catalysts, especially on acarbon carrier, are preferred. It is also preferred that thehydrogenation be carried out in the presence of an inert liquid diluent,for example, methanol, ethanol, dioxane, ethyl acetate, and the like.Hydrogenation pressures ranging from about atmospheric to about 50p.s.i., and hydrogenation temperatures ranging from about 10 to about100 C. are preferred. The resulting 13,14-dihydro product is isolatedfrom the hydrogenation reaction mixture by conventional methods, forexample, removal of the catalyst by filtration or centrifugation,followed by evaporation of the solvent.

Diimide reductions and catalytic hydrogenations to produce the variousnovel Formulas V, IX, XIII, and XVII 13,14-dihydro compounds of thisinvention from the corresponding PGE, PGF, PGF,,, PGA, and PGB typecompounds of the P6,, PG and P6 series are shown in Chart G, wherein D,R R V and W are as defined above.

The free-acid forms of the Formula II-to-V-type compounds are preparedfrom their alkyl esters by enzymatic hydrolysis as follows. Thisprocedure comprises subjecting their alkyl esters to the acylase enzymesystem of a microorganism species of subphylum 2 of Phylum III, andthereafter isolating the acid. Especially preferred for this purpose arespecies of the orders Mucorales, Hypocreales, Moniliales, andActinomycetales. Also especially preferred for this purpose are speciesof the families Mucoraceae, Cunninghamellaceae, Nectreaceae,Moniliaceae, Dematiaceae, Tuberculariaceae, Actinomycetaceae, andstreptomycetaceae. Also especially preferred for this purpose arespecies of the genera Absidia, Circinella, Gongronella, Rhizopus,Cunninghamella, Calonectria, Aspergillus, Penicillium, Sporotrichum,Cladosporium, Fasrium, Nocardia, and Streptomyces. Examples ofmicroorganisms falling within the scope of those preferred orders,families, and genera are listed in US. Pat. No. 3,290,226.

This enzymatic ester hydrolysis is carried out by shaking the PGE-typel5-alkyl ether alkyl ester in aqueous suspension with the enzymecontained in a culture of one of the above-mentioned microorganismspecies until the ester is hydrolyzed. A reaction temperature in therange to C. is usually satisfactory. A reaction time of one to 20 hoursis usually sufficient to obtain the desired hydrolysis. Exclusion of airfrom the reaction mixture for example, with argon or nitrogen is usuallydesirable.

The enzyme is obtained by harvest of cells from the culture, followed bywashing and resuspension of the cells in water, and cell disintegration,for example, by stirring with glass beads or by sonic or ultrasonicvibrations. The entire aqueous disintegration mixture is used as asource of the enzyme. Alternatively and preferably, however, thecellular debris is removed by centrifugation or filtration, and theaqueous supernatant or filtrate is used.

In some cases, it is advantageous to grow the microorganism culture inthe presence of an alkyl ester of an aliphatic acid, said acidcontaining 10 to 20 carbon atoms, inclusive, and said alkyl containingone to 8 carbon atoms, inclusive, or to add such an ester to the cultureand maintain the culture without additional growth for one to 24 hoursbefore cell harvest. Thereby, the enzyme produced is sometimes made moreeffective in transforming the Formula IV ester to the free acid. Anexample of a useful alkyl ester for this purpose is methyl oleate.

This enzymatic hydrolysis is also applicable to the alkyl esters of thePGF-type, PGA-type, and PGB-type 15-alkyl ethers.

When a PG-type 15-alkyl ether acid has been prepared and an alkyl esteris desired, esterification is advantageously accomplished by interactionof the acid with the appropriate diazohydrocarbon. For example, whendiazomethane is used, the methyl esters are produced. Similar use ofdiazoethane, diazobutane, and l-diazo-Z- ethylhexane, for example, givesthe ethyl, butyl, and 2- ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon is a suitable inert solvent, preferablyethyl ether, with the acid reactant, advantagecusly in the same or adilferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example, Organic Reactions, John Wiley &Sons, Inc., New York, N.Y., Vol. 8, pp. 389394 (1954).

The final Formula II-through-XVII l5-alkyl ether PG- type compoundsprepared by the processes of this invention, in free acid form, aretransformed to pharmacologically acceptable salts by neutralization withappropriate amounts of the corresponding inorganic or organic base,examples of which correspond to the cations and amines listed above.These transformations are carried out by a variety of procedures knownin the art to be generally useful for the preparation of inorganic,i.e., metal or ammonium, salts, amine acid addition salts, andquaternary ammonium salts. The choice of procedure depends in part uponthe solubility characteristics of the particular salt to be prepared. Inthe case of the inorganic salts, it is usually suitable to dissolve thePG-type 15-alkyl ether acid in Water containing the stoichiometricamount of a hydroxide, carbonate, or bicarbonate corresponding to theinorganic salt desired. For example, such use of sodium hydroxide,sodium carbonate, or sodium bicarbonate gives a solution of the sodiumsalts. Evaporation of the water or addition of a water-miscible solventof moderate polarity, for example, a lower alkanol or a lower alkanone,gives the solid inorganic salt if that form is desired.

To produce an amine salt, the PG-type acid is dissolved in a suitablesolvent of either moderate or low polarity. Examples of the former areethanol, acetone, and ethyl acetate. Examples of the latter are ethylether and benzene. At least a stoichiometric amount of the aminecorresponding to the desired cation is then added to that solution. Ifthe resulting salt does not precipitate, it is usually obtained in solidform by addition of a miscible diluent of low polarity or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use stoichiometric amountsof the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe PG-type acid with the stoichiometric amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention can be more fullyunderstood by the following examples and preparations:

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin- Elmer model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

NMR spectra are recorded on a varian A-60 spectrophotometer ondeuterochloroform solutions with tetramethylsilane as an internalstandard (downfield).

Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a T-4source (ionization voltage 70 ev.).

Ultraviolet spectra are recorded on a Cary Model spectrophotometer.

The solvent systems used in thin layer chromatography herein include: AIX Ethyl acetate-acetic acid-2,2,4-trimethylpentane-water(90:20:50a100). See M. I-Iamberg and B. Samuelsson, J. Biol. Chem. 241,257 (1966).

Brine as used herein refers to a saturated aqueous solution of sodiumchloride.

Preparation 1.-3a Benzoyloxy 5a hydroxy 4 iodo- 2,8methoxymethylcyclopentaneacetic Acid-y-Lactone (Formula XIX: R isbenzoyl) Refer to Chart A. To a mixture of optically activelaevorotatory iodolactone XVIII (E. I. Corey et al., J. Am. Chem. Soc.,vol. 92, p. 397 (1970), 75 g.) in 135 ml. of dry pyridine under anitrogen atmosphere is added 30.4 ml. of benzoyl chloride with coolingto maintain the temperature at about 40 C. Stirring is continued for anadditional min. About 250 ml. of toluene is added and the mixtureconcentrated under reduced pressure. The residue is dissolved in one 1.of ethyl acetate, washed with 10% sulfuric acid, brine, aqueoussaturated sodium bicarbonate, and brine. The ethyl acetate solution isdried over sodium sulfate and concentrated under reduced pressure toyield an oil, 95 g. Crystalliza tion of the oil yields the titlecompound, m.p. 84-86 0; [@1 +7 (CHCl infrared spectral absorptions at1768, 1722, 1600, 1570, 1490, 1275, 1265, 1180, 1125, 1090, 1060, 1030,and 710 cmr and NMR (nuclear magnetic resonance) peaks at 2.l3.45, 3.3,3:58, 4.38, 5.12, 7.18-7.58, and 783-8056.

Following the procedures of Preparation 1, the optically active FormulaXVIII iodolactone is transformed to a Formula XIX compound using acetylchloride instead of benzoyl chloride, to yield the correspondingintermediate wherein R is acetyl.

Following the procedures of Preparation 1, but replacing that opticallyactive Formula XVIII iodolactone with the racemic compound of thatformula and the mirror image thereof, and employing either benzoylchloride or acetyl chloride, there is obtained the corresponding racemicFormula XIX compound.

Preparation 2.3u Benzoyloxy 50c hydroxy 2Bmethoxymethylcyclopentaneacetic Acid 'y-Lactone (Formula XX: R isbenzoyl) Refer to Chart A. To a solution of the optically active FormulaXIX benzoxy compound (Preparation 1, 60 g.) in 240 ml. of dry benzene isadded 2,2-azobis-(2-methylpropionitrile) (approximately 60 mg.). Themixture is cooled to 15 C. and to it is added a solution of 75 g.tributyltin hydride in 600 ml. of ether, with stirring, at such a rateas to maintain continuous reaction at about 25 C. When the reaction iscomplete as shown by TLC (thin layer chromatography) the mixture isconcentrated under reduced pressure to an oil. The oil is mixed with 600ml. of Skellysolve B (isomeric hexanes) and 600 ml. of water and stirredfor 30 min. The water layer, containing the product, is separated, thencombined with 450 ml. of ethyl acetate and enough solid sodium chlo rideto saturate the aqueous phase. The ethyl acetate layer, now containingthe product, is separated, dried over magnesium sulfate, andconcentrated under reduced pressure to an oil, 39 q. of the titlecompound. An analytical sample gives [oc] -99 (CHCl infrared spectralabsorptions at 1775, 1715, 1600, 1585, 1490, 1315, 1275, 1180, 1110,1070, 1055, 1025, and 715 cmr NMR peaks at 2.15-3.0, 3.25, 3.34,4.84-5.17, 5.17-5.4, 7.1- 7.5, and 78-8056; and mass spectral peaks at290, 168, 105, and 77.

Following the procedures of Preparation 2, each of the optically activeFormula X'IX compounds or their racemic compounds following Preparation1 is transformed to the corresponding optically active Formula XXcompound or its racemic compound.

Preparation 3.- 3m Benzoyloxy 5a hydroxy- 2,8hydroxymethylcyclopentaneacetic Acid 'y-Lactoue (Forula XXI: R isbenzoyl) Refer to Chart A. To a cold (0-5" C.) solution of lactone XX(Preparation 2, 20 g.) in 320 ml. of dichloromethane under nitrogen isadded a solution of 24.8 ml. of boron tribromide in 320 ml. ofdichloromethane, dropwise with vigorous stirring over a period of 50min. at 0-5 C. Stirring and cooling are continued for 1 hr. When thereaction is complete, as shown by TLC, there is cautiously added asolution of sodium carbonate (78 g. monohydrate) in 200 ml. of water.The mixture is stirred at 0-5 C. for 10-15 min., saturated with sodiumchlo ride, and the dichloromethane layer separated. Additional ethylacetate extractions of the water layer are combined with thedichloromethane solution. The combined solutions are rinsed with brine,dried over sodium sulfate and concentrated under reduced pressure to anoil, 18.1 g. of the title compound. An analytical sample has m.p.116-118 C.; [ab -SO" (CHCl infrared spectral absorptions at 3460, 1735,1708, 1600, 1580, 1490, 1325, 1315, 1280, 1205, 1115, 1090, 1070, 1035,1025, 730, and 720; and NMR peaks at 2.1-3.0, 3.58, 4.83-5.12, 5.2-5.45,7.15-7.55, and 78-806.

Following the procedures of Preparation 3, each of the optically activeFormula XX compounds or their racemic compounds following Preparation 2is transformed to the corresponding optically active Formula XXIhydroxymethyl compound or its racemate.

Preparation 4.-3a-Benzoyloxy-2i8-carboxaldehyde5ozhydroxy-cyclopentaneacetic Acid 'y-Lactone (Formula XXII: R isbenzoyl).

Refer to Chart A. To a mixture of 150 ml. of dry dichloromethane andCollins reagent (J. C. Collins et al., Tetrahedron Lett. 3363 (1968), 28g.) at about 10 C. under nitrogen is added, with vigorous stirring, acold (10 C.) solution of the optically active hydroxymethyl lactone XXI(Preparation 3, 5.0 g.) in 150 ml. of dichloromethane. After S-min.addititonal stirring, about 100 ml. of dry benzene is added, the mixtureis filtered, and the solution is concentrated under reduced pressure.The volume is brought to about 150 ml. with benzene. The solution of theFormula XXII title compound is used directly.

From a similar run, there is obtained by concentration of the benzenesolution under reduced pressure an oil which, on trituration with ether,yields crystals of the optically active Formula XXII compound, m.p. C.

27 (dec.) and having NMR peaks at 1.8-3.7, 4.9-5.2, 5.54- 5.77, 7.2-7.6,7.7-8.0, and 9.86.

Following the procedures of Preparation 4, each of the optically activeFormula XXI hydroxymethyl compounds or their racemic compounds followingPreparation 3 is transformed to the corresponding optically activeFormula XXII aldehyde or its racemate wherein R is either benzoyl oracetyl.

Preparation 5.-3a-Benzoyloxy-5a-hydroxy-2/3-(3oxotrans-l-octenyl)-la-cycopentaneacetic Acid -Lactone (Formula XXIII: Ris benzoyl).

Refer to Chart A. A solution of dimethyl 2-oxo-heptylphosphonate (Coreyet al., Journal of the American Chemical Society, 90, 3247 (1968)), in36 ml. of THF is added, with stirring, to a cold (5 C.) suspension ofsodium hydride (55%, 162 g.) in 180 ml. of THF. Thereafter the reactionmixture is stirred at about 25 C. for 2.5 hrs., and cooled to C. To themixture is added a benzene solution of optically active aldehyde XXII(Preparation 4, 108 ml.). After 1.5 hrs., 1.8 ml. of acetic acid isadded and the THF distilled under vacuum. The residue is dissolved inethyl acetate and the solution is washed with brine, dried over sodiumsulfate, and concen trated under reduced pressure. Chromatography oversilica gel using 25-30% ethyl acetate in Skellysolve B (isomerichexanes) for elution yields the Formula XXIII title compound.

Following the procedures of Preparation 5, but replacing the aldehydeXXII with each of the optically active Formula XI aldehydes or theirracemates disclosed following Preparation 4 there are obtained thecorresponding Formula XXIII compounds wherein R corresponds to the Rmoiety on the Formula XXII aldehyde. The racemic Formula XXII aldehydeseach yield a corresponding Formula XXIII racemate.

Preparation 6.-3ot-Benzoyloxy-5a-hydroxy-2B-(3a hydroxy-transl-octenyl)-la-cyclopentaneacetic Acid Lactone (Formula XXIV: R is benzoyl, and isalpha).

Refer to Chart A. A solution containing ketone XXIII (Preparation 5,2.75 g.) in 14 ml. of 1,2-dimethoxyethane is added to a mixture of zincborohydride prepared from zinc chloride (anhydrous, 4.9 g.) in sodiumborohydride (1.12 g.) in 48 ml. of dry 1,2-dimethoxyethane, withstirring and cooling to -10 C. Stirring is continued for 2 hrs. at 0 C.,and water (7.8 ml.) is cautiously added, followed by 52 ml. of ethylacetate. The mixture is filtered, and the filtrate is separated. Theethyl acetate solution is washed with brine, dried over sodium sulfate,and concentrated under reduced pressure to a mixture of thecorresponding Formula XXIV alpha and beta isomers. The compounds aresubjected to chromatography on a silica gel column, eluting with ethylacetate, to separate the alpha (less polar) and beta isomers of theFormula XXIV title compounds.

Following the procedures of Preparation 6, the optically active FormulaXXIII ketones or their racemic mixtures described following Preparation5, wherein R is benzoyl or acetyl, are transformed to the correspondingoptically active Formula XXIV hydroxy compounds or their racemates.

Example 1.-3a-Benzoyloxy-Sa-hydrOXy-ZB-(3amethoxy-trans-l-octenyl)-lot-cyclopentaneacetic Acid Lactone (FormulaXXV: R is methyl and R is benzoyl).

Refer to Chart A where formulas for compounds XVIII through XXVI areshown. A mixture of the Formula XXIV alpha hydroxy compound (Preparation6, 2.0 g.), silver oxide (4.0 g.), and 50 ml. of methyl iodide isstirred and heated at reflux for 68 hrs. The mixture is cooled andfiltered, and the filtrate concentrated to an oil, 2.0 g. Separation bysilica gel chromatography, eluting with 35% ethyl acetate-Skellysolve Band combining those fractions shown by TLC to contain the product freeof starting material and impurities, yields the Formula XXV titlecompound as a yellow oil, 1.16 g. Infrared absorption at 1775, 1720,1600, 1585, 1490, 1315, 1275, 1175, 1115, 1100, 1070, 1050, 1025, 970,and 715 CITLTI; NMR peaks at 0.8 (broad), 1.4 (broad), 1.9 (broad), 2.3(broad), 2.7 (broad), 3.15 (singlet), 5.1 (broad), 5.4-5.6 (triplet),7.5 (broad), and 7.8-8.0 (multiplet) 6.

Following the procedures of Example 1, but replacing the methyl iodideof that example with other alkyl halides, there are obtained thecorresponding Formula XXV alkyl ethers. Thus, with methyl bromide, ethylcholride, isopropyl iodide, butyl bromide, or pentyl iodide, there areobtained the Formula XXV compound in which R is methyl, ethyl,isopropyl, n-butyl or n-pentyl.

Following the procedures of Example 1 and using either methyl iodide orthe alkyl halides in the paragraph above, each of the optically activeor racemic Formula XXIV hydroxy compounds following Preparation 6,wherein R is benzoyl or acetyl, is transformed to the correspondingoptically active Formula XXV alkyl ether compound or racemate consistingof that compound and its mirror image.

Example 1A.-3a-Benzoyl-2fl-(3a-tert-butoxytrans 1-octenyl)-1a-cyclopentaneacetic Acid 'y-Lactone (Formula XXV: R istert-butyl and R is benzoyl).

Refer to Chart A. To a mixture of the Formula XXIV alpha-hydroxycompound, viz. 3a-benzoyloxy-5u-hydroxy2fl-(3a-hydroxy-tr'ans-l-octenyl)-la-cyclopentaneacetic acid -lactone(Preparation 6, 2.0 g.) in 25 ml. of pyridine under nitrogen at 0 C.,there is slowly added with stirring 4 -ml. of methanesulfonyl chlorideover a 15 min. period. Thereafter the mixture is stirred at 0 C. for 2.5hrs., then cooled to l5 C. and mixed with 10 ml. of ice and water. Afterabout 5 'min., the mixture is poured into 250 ml. of ice and water. Cold1:3 dichloromethane-ether mixture ml.) is added, followed by ml. of cold3N hydrochloric acid. The organic layer is removed, washed with 2%sulfuric acid, water, aqueous sodium bicarbonate, and brine, then driedover sodium sulfate and concentrated under reduced pressure to the3a-mesyloxy intermediate.

To a mixture of the above intermediate (2.2 g.) and pyridine (20 ml.) isadded a mixture tert-butoxide (0.55 g.) and benzene (10 ml.) and theresulting mixture is stirred for several hours at about 25 C. undernitrogen. Thereafter the mixture is cautiously poured into 100 ml. ofwater and neutralized with cold 3 M hydrochloric acid. The mixture isextracted with benzene and the benzene extracts are combined, washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated. The residue is separated by silica gel chromatography,eluting with 35% ethyl acetate-Skelly-solve B and combining thosefractions shown by TLC to contain the product free of starting materialand impurities, to yield the Formula XXV title compound.

Following the procedures of Example 1A, but replacing potassiumtert-bu-toxide with sodium ethoxide, potassium isopropoxide, or sodiumtert-pentyloxide, and using either the benzoyl or acetyl form of theFormula XXIV compound, there is obtained the corresponding Formula XXVcompound wherein R is ethyl, isopropyl, or tertpentyl and R is benzoylor acetyl,

Example 2.-3ot,5ot 'Dihydroxy-Zfi-(3a-methoxy-trans-1-octenyl)-1u-cyclopentaneacetic Acid 'y-lactone (Formula XXVI: R ismethyl) Refer to Chart A. A mixture of the Formula XXV benzoyl-oxycompound (1.91 g.) and anhydrous potassium carbonate (0.684 g.) in 25ml. of dry methanol is stirred for 1 hr. with exclusion of moisture.Chloroform (25 ml.) is added and the mixture is filtered. The filtrateis concentrated to an oil which is taken up in chloroform '(50 ml.). Thesolution is washed with brine, dried over magnesium sulfate, andconcentrated to an oil. Separation by silica gel chromatography, elutingwith 40% ethyl acetate-Skellysolve B and combining those fractions shownby TLC to contain the product free of starting material and impurities,yields the Formula XXVI title compound as a pale yellow oil, 1.0 g. Massspectral peaks at 250, 211, 193, and 179; infrared spectral absorptionat 3420, 1765, 1175, 1090, 1035, 975, and 905 cm.- NMR peaks at 0.8-.1(multiplet), 1.4 '(broad), 1.9-2.4 (multiplet), 3.3 (singlet), 4.1(multiplet), 5.1 (multiplet) and 5.5 (multiplet) 6. A sample isrecrystallized from ether- Skellsolve B as needles, mp. 57.5-60 C.

Following the procedures of Example 2, each of the Formula XXV alkylether compounds described following Example 1 and 1A is transformed tothe corresponding optically active Formula XXVI alkyl ether compound orracem-ate consisting of that compound and its mirror image. For example,the Formula XXV compounds wherein R is ethyl, isopropyl, butyl,tert-butyl, n-pentyl, or tert-pentyl yield the corresponding Formula)Q(VI compounds wherein R is ethyl, isopropyl, n-butyl, tertbutyl,n-pentyl, or tert-pentyl.

Example 3.PGE 15-Methyl Ether (Formula III. R is hydrogen and R ismethyl) Refer to Chart B, wherein steps (a) through (e) are shown, andformulas for compounds XXVI through XXXI, wherein R is methyl.

(a) The tertahydropyr-anyl (THP) ether is prepared as follows. A mixtureof the Formula XXVI 3a,5a-dihydroxy-2/3-(3a-methoxytrans-l-octenyl)-1a-cyclopentaneacetic acid -lactone (2.35 g.),dihydropyran (3.5 g.), and p-toluene-sulfonic acid (about 0.01 g.) in150 ml. of dichloromethane is stirred for 30 min. The mixture is washedtwice with sodium carbonate solution, and brine, and dried overmagnesium sulfate. Concentration under reduced pressure yields theFormula XXVII THP ether, 3.26 g., free of starting material by TLC.

(b) The Formula XXVIII lactol is prepared as follows. To a solution ofthe above THP ether in 150 ml. of dry toluene is added with stirring,protecting from air with nitrogen, a solution (105 ml.) ofdiisobutylaluminum hydride (10% in toluene) in about 35 min. at about 60C. stirring is continued for 30 min., with cooling. The cooling bath isremoved, and a mixture of 48 ml. of tetrahydrofuran (THF) and 29 ml. ofwater is added dropwise over 20 min. The mixture is filtered, and thefiltrate is washed with brine and dried over magnesium sulfate.Concentration under reduced pressure yields the Formula XXVIII lactol asa yellow oil, 3.11 g., free of lactone by TLC.

(c) The Formula XXDC compound is obtained with a a Wittig reagentprepared as follows. 4-Carboxybutyl triphenylphosphonium bromide (7.36.g.) obtained from Hal-(CH COOH wherein Hal is bromo or chloro bymethods known in the art is added to a solution of sodiodimethyl-sulfinylcarbanide prepared from sodium hydride (57%, 1.4 g.)and 30 ml. of dimethylsulfoxide (DMSO), and the mixture is stirred for20 min. at about 36 C. To this reagent is added dropwise the FormulaXXVIII lactol of step (b) (3.11 g.) in 25 ml. of DMSO. The mixture isstirred at about 25 C. for 3.5 hrs., then diluted with about 30 ml. ofbenzene. To it is added dropwise a solution of potassium hydrogensulfate (5.96 g.) in 57 ml. of water with cooling and stirring. Themixture is diluted with 200 ml. of water and 100 ml. of benzene,separated, and the organic layer is washed with water and dried overmagnesium sulfate. Concentration under reduced pressure yields an oilwhich is stirred with ether to further separate some solid by-products.Evaporation of the ether yields an oil which is separated by silica gelchromatography, eluting with 40% ethyl acetate-Skellysolve B, andcombining those fractions shown by TLC to be free of starting materialand impurities. yield of Formula XXIX compound, a yellow oil, 2.07 g.

(d) The Formula XXIX compound is oxidized to the Formula XXX9-oxo-compound as follows. To a solution of the 11THP, IS-methyl ethercompound of step (c) (0.877 g.) in 20 ml. of acetone at -20 C. is addeddropwise 1.0 ml. of Jones reagent (2.1 g. of chromic anhydride, 6 ml. ofwater, and 1.7 ml. of concentrated sulfuric acid). After 15 min.stirring, 1 ml. of 2-propanol is added, with additional stirring. Themixture is poured into ml. of water and extracted with dichloromethane.The organic extracts are washed with brine, dried over magnesiumsulfate, and concentrated under reduced pressure to the Formula XXXcompound.

(e) The Formula XXX ll-THP compound is hydrolyzed to the Formula XXXIPGE IS-methyl ether, compound as follows. The product of step (d) isdissolved in a mixture of 20 ml. of acetic acid, 10 ml. of water, and 3ml. of THF, and left standing at about 40 C. for 3 hrs. An additional 50ml. of water is added, and the mixture is frozen and then freeze-driedunder reduced pressure. Separation of the residual oil by silica gelchromatography, eluting with 40% ethyl acetate-Skellysolve B andcombining those fractions shown by TLC to be free of starting materialand impurities, yields the Formula HI, title compound as a tan oil, 0.4g. Mass spectral peaks at 348, 334, 330, 316, 298, and 277; infraredspectral absorptions at 3420, 3300-3100, 2650, 1735, 1710, 1285, 1240,1155, 1085, 1075, and 970 cmf NMR peaks at 0.8-1.1 (multiplet), 1.4(broad), 2.3 (broad), 3.3 (singlet), 3.4-3.6 (multiplet), 4.0-4.2(multiplet), and 5.5 (broad) 6.

Following the procedures of Example 3, each of the optically activeFormula XXVI alkyl others or their racemic compounds following Example 2is transformed to the corresponding Formula XXIX intermediate and thencethe Formula XXXI PGE lS-alkyl ether. For example, the optically activeFormula XXVI compound wherein R2 is isopropyl yields PGE 15-isopropylether; the racemate of the Formula XXVI compound wherein R is butylyields racemic PGE 15-butyl ether. In like manner, there are preparedother Formula XXIX intermediates and Formula III PGE -type productswherein R is hydro gen and R is alkyl of one to 5 carbon atoms,inclusive, e.g. PGE 15-ethyl ether, and PGE 15-pentyl ether.

Example 4.-PGF 15-Methyl Ether (Formula VII: R is hydrogen, R is methyl,and is alpha) Refer to Chart C, wherein R is methyl. The Formula XXIXTHP-ether intermediate is hydrolyzed as follows. A mixture of theTHP-ether (Example 3, step c, 2.07 g.), 40 ml. of acetic acid, 20 ml. ofwater, and 6 ml. of THF is maintained at about 38 C. for 4.5 hrs. Anadditional 100 ml. of water is added, and the mixture is frozen and thenfreeze-dried under reduced pressure. Separation of the residualoil-solids mixture by silica gel chromatography, eluting with 40% ethylacetate-Skellysolve B and combining those fractions shown by TLC to befree of starting materials and impurities yields the Formula VII titlecompound, 1.2 g. Crystallization from ether-Skellysolve B yieldscrystals, mp. 52-55 C. Mass spectral peaks at 353, 350, 336, 318, 300,264, and 261; infrared spectral absorptions at 3420, 2950, 2720, 2660,1715, 1680, 1330, 1270, 1205, 1130, 1075, 980, and 925 cmr NMR peaks at0.8-1.1 (multiplet), 1.5 (broad), 2.2 (broad), 3.3 (singlet) 4.0-4.3(multiplet), and 5.5 (broad) 6.

Following the procedures of Example 4, but replacing that Formula XXIXintermediate with those Formula XXIX intermediates described followingExample 3, there are obtained the corresponding optically active FormulaVII (XXXII) PGF alkyl ether products, for example PGF 15-isopropylether; racemic PGF l5-butyl ether; PG z 15-methyl ether; and the like,wherein R is within the scope as defined herein.

3-1 Example 5.PGE Methyl Ester, IS-Methyl Ether (Formula II: R and R aremethyl) Refer to Chart D, wherein D is E is -CH=CH, R and R are methyl,R is hydrogen, V is (CH and W is l-pentyl. A mixture of PGE (0.25 g.),silver oxide (1.2 g.) and 50' ml. of methyl iodide is stirred and heatedat reflux for 2 days. The mixture is cooled and filtered, and thefiltrate concentrated. The residue is separated by silica gelchromatography, eluting with acetone-dichloromethane. Those fractionsshown by TLC to contain the -methyl ether compound free of startingmaterials and impurities are combined and concentrated to yield theFormula II (XXXIV) title compound. The PGE methyl ester, IS-methyl etherhas mass spectral peaks at 364, 332, 301, 300, and 293.

Following the procedure of Example 5, but replacing PGE with PGE or13,14-dihydro-PGE there are obtained the corresponding methyl ester,15-methyl ether compounds of PGE and 13,14-dihydro-PGE Likewisefollowing the procedure of Example 5 but replacing PGE with racemic PGEracemic PGE or racemic 13,14-dihydro-PGE there are obtained thecorresponding methyl ester, 15-methyl ether compounds of these racemicPGE compounds.

Likewise following the procedure of Example 5 but replacing the methyliodide of Example 5 with other alkyl iodides, and employing either PGEPGE PGE or 13,14-dihydro-PGE there are obtained the correspondingFormula XXXIV alkyl ester, 15-alkyl ether PGE-type compounds.

Likewise following the procedure of Example 5 but replacing PG-E withPGF PGF PGF PGF PGF PGF 13,14-dihydro-PGF or 13,14-dihydro-PGF or theirracemates, there are obtained the corresponding methyl ester, IS-methylether PGF-type compounds Within the scope of Formula XXXIV and theirracemates.

Example 5A.-PGE Methyl Ester, lS-Methyl Ether (Formula III: R and R aremethyl) Refer to Chart D, wherein D is E is CH=CH--, R and R are methyl,R is hydrogen, V is CH=CH(CH and W is l-pentyl. A solution of PGE (1.6g.) in 150 ml. of dichloromethane is treated at about C. with an ethersolution of diazomethane containing 0.5 ml. of boron trifluorideetherate (see Fieser et al., Reagents for Organic Synthesis, p. 192,John Wiley & Sons, Inc., New York, N.Y. (1967)) until the bright yellowdiazomethane color persists for 10 min.

Excess diazomethane is destroyed with a few drops of acetic acid and thesolvent is removed under reduced pressure. The residue is separated intocomponents by silica gel chromatography. Those fractions shown tocontain the title compound free of the methyl ester of the startingcompound and by-products by thin layer chromotography (TLC) are combinedto yield the Formula III (XXXIV) title compound.

Following the procedures of Example 5A, but replacing the PGE of thatexample with PGE PGE or 13,14-

32 dihydro-PGE there are obtained the corresponding methyl ester,IS-methyl ether compounds of PGE PGE/ or 13,14-dihydro-PGE Likewisefollowing the procedures of Example 5A, but replacing the diazomethaneof that example with other diazoalkanes, there are obtained thecorresponding Formula XXXIV alkyl ester, lS-alkyl ether PGE-typeproducts. Thus, with diazoethane, diazopropane, or diazobutane, and PGEthere are obtained the corresponding Formula III (XXXIV) products: PGEethyl ester, 15- ethyl ether; PGE propyl ester, 15-propyl ether; and PGEbutyl ester, IS-butyl ether. Starting with PGE methyl ester, yields PGEmethyl ester, 15-ethyl ether; PGE methyl ester, 15-propyl ether; and PGEmethyl ester, IS-butyl ether.

Example 5B.PGF Methyl Ester, 15-Methyl Ether (Formula VII: R and R aremethyl and is alpha).

Refer to Chart D wherein D is E is -CH=CH-, R R and R are methyl, V isCH=CH-(CH and W is l-pentyl. A solution of PGF methyl ester (1.0 g.) in20 ml. of methanol is treated with boron trifluoride etherate (0.25 ml.)at about 25 C. and left standing for 1 hr. Water (about 10 ml.) is addedand the mixture is concentrated under vacuum to remove most of themethanol. The residue is extracted with ethyl acetate and the combinedethyl acetate extracts are washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis taken up in a small amount of dichloromethane and separated by silicagel chromatography, to yield the Formula XII (XXXIV) title compound.

Following the procedure of Example 5B, but replacing PGF methyl ester,with the ethyl, propyl, isobutyl, and heptyl esters of PGF- there areobtained the corresponding ethyl, propyl, isobutyl, and heptyl esters ofPGF 15- methyl ether.

Likewise following the procedure of Example 5B, but replacing P'GFmethyl ester, with racemic PGF methyl ester, there is obtained racemicPGF methyl ester, 15- methyl ether. Likewise the ethyl propyl isobutyl,and heptyl esters of racemic IPGF yield the corresponding esters ofracemic PGF IS-methyl ether.

Likewise following the procedure of Example 5B, but replacing themethanol of that example with other alcohols, e.g. ethanol, propanol,butanol, or pentanol, there are obtained the corresponding PGF alkylester, 15- alkyl ether compounds wherein R is ethyl, propyl, butyl orpentyl.

Example 6.PGA Methyl Ester, Methyl Ether (Formula XI: R and R aremethyl).

Refer to Chart D wherein D is E is CH=CH, R and R are methyl, R ishydrogen, V is CH=CH-(CH and W is 1 pentyl. A mixture of PGA (0.237 g.),silver oxide (0.41 g.), and 40 ml. of methyl iodide is stirred andheated at reflux for 17 hrs. The mixture is cooled and filtered, and thefiltrate concentrated to a yellow oil. Separation by silica gelchromotography, eluting with 0.5-1.0% methanol-dichloromethane, yieldsthe Formula XI title compound, 0.04

g., as a yellow oil. Mass spectral peaks at 331, 330, 291, and 250; inethanol, 217 (e=9,300) and 274 (e=1,550) mu.

Following the procedure of Example 6, PGA PGA and dihydro PGA, areconverted to the corresponding Formula-XI compounds, for example PGAmethyl ester, methyl ether, and the like.

Example 6A.PGA 15-(tert-Butyl) Ether, Methyl Ester (Formula X: R ismethyl and R is tert-butyl).

To a solution of PGA methyl ester (5.0 g.) in 50 ml. of pyridine at C.under nitrogen is added slowly with stirring 7 ml. of methanesulfonylchloride over a period of 15 min. Thereafter the mixture is stirred at 0C. for 2.5 hrs., then cooled to 15" C. and mixed with 10 ml. of ice andwater. After about min, the mixture is poured into 500 ml. of ice andwater. Cold 1:3 dichloromethaneether mixture (200 ml.) is added,followed by 300 ml. of cold 3 M hydrochloric acid. The organic layer isremoved, washed with 2% sulfuric acid, water, aqueous sodiumbicarbonate, and brine, then dried over sodium sulfate and concentratedunder reduced pressure to yield the 15- mesylate.

To a mixture of the 15-mesylate (4.13 g.) and pyridine (30 ml.) is addeda mixture of potassium tert-butoxide (1.12 g.) and benzene (20 ml.), andthe resulting mixture is stirred for several hours at about 25 C. undernitrogen. Thereafter the mixture is cautiously poured into 200 m1. ofwater and neutralized with cold 3 M hydrochloric acid. The mixture isextracted with benzene and the benzene extracts are combined, washedwith water and brine, dried over anhydrous sodium sulfate, andconcentrated. The residue is separated by silica gel chromatography,eluting with 50100% ethyl acetate Skellysolve B and combining thosefracitons shown by TLC to contain the desired 15u-(tert-buyl) ether,thereafter concentrating under reduced pressure to yield the Formula Xtitle compound.

Example 7.-PGB Methyl Ester, Methyl Ether (Formula XV: R and R aremethyl) Refer to chart D wherein D is E is --CH-=CH, R and R are methyl,R is hydrogen, V is CH=CH-(CH and W is l-pentyl. A solution of PGB (1.63g.) is stirred with silver oxide (5 g.), methyl iodide (20 m1.), and 200ml. of benzene and heated at reflux under a water separator for 18 hrs.The mixture is filtered, and the filtrate concentrated to a yellow oil.Separation by silica gel chromatography, eluting with 2%acetone-dichloromethane, yields the Formula XV title compound, 0.3 g.,as a yellow-brown oil. Ultraviolet absorption: A in ethanol, 277 (6 25,-450 )m Mass spectral peaks at 331, 330, and 29-1.

Folowing the procedure of Example 7, PGB PGB and dihydro-PGB areconverted to the corresponding Formula XV compounds, for example PGBmethyl ester, methyl ether, and the like.

Example 8.PGF Methyl Ester, 15 Methyl Ether (Formula VI: R and R aremethyl and is alpha) and PGF Methyl Ester, l5-Methyl Ether (Formula VI:is beta) Refer to Chart E wherein E is -CH=CH, R and R are methyl, V is--(CH W is l-pentyl, and is either alpha or beta. A solution of sodiumborohydride (0.6 g.) in 10 ml. of methanol at 0 C. is addedto a solutionof PGE methyl ester, IS-methyl ether (Example 5, 1.5 g.) in 60 ml. ofmethanol and the mixture is stirred at 0 C. for 30 minutes. Acetone (10ml.) is

added and the solution is made slightly acid with dilute acetic acid inmethanol. The mixture is concentrated by evaporation under reducedpressure and the residue is taken up in dichloromethane. The resultingsolution is washed with brine, dried over sodium sulfate and evaporatedunder reduced pressure. The residue is chromatographed over silica gelwet-packed in 8% methanol in dichloromethane and rinsed with 300 ml. ofdichloromethane, eluting with 2-10% methanol-dichloromethane. Thosefractions shown by TLC to contain PGF methyl ester, IS-methyl ether freeof starting material and impurities are combined and concentrated toyield the Formula VI PGF ,-type title compound. Likewise, thosefractions shown by TLC to contain PGF methyl ester, 15-methyl ether arecombined and concentrated to yield the formula VI PGF -type titlecompound.

Following the procedures of Example 8, each of the PGE alkyl ester,15-alkyl ether compounds of and following Examples 3, 5, and 5A istransformed to the corresponding PGF, and PGF, optically active andracemic compounds.

Example 8A.--PGF Methyl Ester, 15-Methyl Ether (Formula VII: R and R aremethyl, and is alpha) and PGF Methyl Ester, IS-Methyl Ether (FormulaVII: is bet-a) Refer to Chart F, wherein E is CH=CH-, R R and R aremethyl, R7 is (CH Si-, V is W is l-pentyl, and is alpha or beta. Asolution of PGE methyl ester, 15-methyl ether (Example 1, 1.0 g.) in 20ml. of dry tetrahydrofuran (THF) is stirred with 3 ml. ofhexamethyldisilazane and 0.6 ml. of trimethyl chlorosilane for 20 hrs.at about 25 C., with protection from moisture. The mixture isconcentrated under reduced pressure, then taken up in 50 m1. of drybenzene and again concentrated. The residue is dissolved in 150 ml. ofcold methanol and treated, with stirring, with a cold (-l0 C.) solutionof sodium borohydride (2.8 g.) in 150 ml. of methanol, maintaining thetemperature below about 10 C. After 10 minutes of additional stirring,there is added 5 ml. of acetone and sufiicient acetic acid to neutralizethe mixture. The mixture is concentrated under reduced pressure to aboutml. Water (about 75 ml.) is added to hydrolyze the trimethylsilyl groupthereafter stirring at about 25 C. for 3 hrs. When the trimethylsilylgroup is removed, as shown by TLC, the mixture is concentrated underreduced pressure to remove most of the methanol. The remaining solutionis extracted with ethyl acetate, and the combined ethyl acetate extractsare washed with brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is taken up in aminimum amount of dichloromethane and-sub- J'EEted to silica gelchromatography, eluting with 50- ethylacetate-Skellysolve B (isomerichexanes). Those fractions shown to contain the 9a-hydroxy title compoundfree of starting compound and by-products by TLC are combined to yieldthe PGF ,-type Formula VII title compound. Mass spectral peaks at 382,364, 350, 346 and 332; infrared spectral absorptions at 3410, 1735,1660, 1435, 1365, 1315, 1240, 1215, 1195, 1170, 1090, and 970 cmr NMRpeaks at 5.42 (multiplet), 3.9 (multiplet), 3.64, 3.49, 3.21, and 0.9(triplet) 6.

Likewise, those fractions shown by TLC to contain PGF methyl ester,IS-methyl ether are combined and concentrated to yield the Formula VHPGF -type title compound.

Following the procedures of Example 8A, but replacing PGE methyl ester,15-methy1 ether with PGE 15- rnethyl ether (Example 3) there is obtainedPGE 15- methyl ether. Likewise, each of the esters of PGE;;, 15- methylether, described following Example 3 yields the corresponding ester ofPGF IS-methyl ether.

- 3 Example 9.PGA Methyl Ether (Formula X: R is hydrogen and R ismethyl) Refer to Chart E, wherein E is --CH=CH, R is methyl, R ishydrogen, V is -(CH and W is 1- pentyl. A mixture of PGE IS-methylether, (0.4 g.), glacial acetic acid (9 ml.), and water (1 ml.) isheated under nitrogen at 60 C. for 18 hrs. The mixture is concentratedunder reduced pressure, and the residue is subjected to silica gelchromatography, eluting with ZS-100% ethyl acetate-Skellysolve B. Thefractions shown by TLC to contain the desired productfree of startingmaterial and impurities are combined and concentrated to give theFormula X PGA -type title compound.

Following the procedures of Example 9, each of the PGB-type compoundsdescribed following Examples 3, 5, and 5A is transformed to thecorresponding PGA-type alkyl ether.

Example 10.PGB Methyl Ether (Formula XIV: R is hydrogen and R is methyl)Refer to Chart E, wherein E is CH=CH-, R is methyl, R is hydrogen, V is-(CH and W is l-pentyl. A mixture of PGE IS-methyl ether (0.2 g.),potassium hydroxide (10 g.), and 100 ml. of 50% aqueous ethanol ismaintained at about 25 C. for 10 hrs, under nitrogen. The mixture isthen cooled to 10 C. and neutralized by addition of 3 N hydrochloricacid at 10 C. The resulting solution is extracted repeatedly with ethylacetate, and the combined ethyl acetate extracts are washed with waterand brine, dried, and concentrated to the Formula XIV PGB -type titlecompound.

Following the procedures of Example 10, each of the PGB-type compoundsdescribed following Examples 3, 5, and 5A is transformed to thecorresponding PGB-type alkyl ether.

Example l1.-13,14-Dihydro-PGE -Methyl Ether (Formula V: R is hydrogenand R is methyl) Refer to Chart G wherein D is R is methyl, R ishydrogen, V is (CH and W is l-pentyl. A solution of PGE IS-methyl ether(100 mg.) in 10 ml. of ethyl acetate is shaken with hydrogen at aboutone atmosphere pressure at 25 C. in the presence of 5% palladium oncharcoal (15 mg.). One equivalent of hydrogen is absorbed in about 90minutes. The hydrogenation is then stopped, and the catalyst is removedby filtration. The filtrate is evaporated, and the residue ischromatographed on 25 g. of silica gel, eluting with a 50-100% ethylacetate gradient in Skellysolve B. Those fractions shown .by TLC tocontain the desired product free of the starting product and dehydrationproducts are combined and evaporated to give the Formula V13,14-dihydro-PGE -type title compound.

Following the procedure of Example 11, PGE 15- methyl ether, ethyl esteris reduced to 13,14-dihydro- PGE IS-methyl ether, ethyl ester.

Also following the procedure of Example 11, PGE IS-methyl ether, and PGEIS-methyl ether, are each reduced to 13,14-dihydro-PGE 15-methyl etherusing two equivalents of hydrogen for the first reaction and threeequivalents of hydrogen for the second.

Also following the procedure of Example 11, the ethyl ester and the freeacid form of the Formula II-to-IV PGE compounds, IS-alkyl ethers,transformed to the corresponding 13,14-dihydro PGE 15-alkyl ethercompounds by catalytic hydrogenation, using equivalents of hydrogenappropriate to the degree of unsaturation of the reactant,

36 i.e., one equivalent for the PGE -type, two equivalents for the PGE-type, and three equivalents for the PGE type compounds.

Also following the procedure of Example 11, PGF IS-methyl ether, and itsethyl ester are reduced to 13,14- dihydro-PGF 15-methyl ester, and itsethyl ester, respectively.

Also following the procedure of Example 11, the ethyl ester and the freeacid form of the Formula VI-to-VIII PGF 15-alkyl ester compounds aretransformed to the corresponding 13,14-dihydro PGF or PGF 15-alkyl estercompounds by catalytic hydrogenation, using equivalents of hydrogenappropriate to the degree of unsaturation of the reactant.

Example 12.13,14-Dihydro-PGA Methyl Ether (Formula XIII: R is hydrogenand R is methyl) Refer to Chart G wherein D is R is methyl, R ishydrogen, V is -(CH and W is 1 pentyl. A suspension of disodiumazodiformate (50 mg.) in 5 ml. of absolute ethanol is added to a stirredsolution of PGA methyl ether (50 mg.) in 10 ml. of absolute ethanolunder nitrogen at 25 C. The mixture is made acid with glacial aceticacid, and then is stirred under nitrogen at 25 C. for 8 hours. Theresulting mixture is evaporated under reduced pressure and the residueis mixed with a mixture of diethyl ether and water (1:1). The diethylether layer is separated, dried, and evaporated to give the Formula-XIII13,14-dihydro PGA type title compound.

Following the procedure of Example 12, PGA methyl ester, methyl ether isreduced to l3,l4-dihydro-PGA methyl ester, methyl ether.

Also following the procedure of Example 12, PGA;, methyl ether, and PGAmethyl ether, are each reduced to 13,14-dihydro-PGA methyl ether, usingamounts of the disodium azodiformate reactant appropriate to the degreeof unsaturation of the reactant.

Also following the procedure of Example 12, the methyl ester and thefree acid form of the 15-alkyl ethers of the Formula II-to-IV PGE-typecompounds, the Formula VI- to-VIII PGF compounds, the Formula X-to-XIIPGA compounds, and the Formula XIV-to-XVI PGB compounds are transformedto the corresponding 13,14-dihydro PGE PGF PGA or PGB -type IS-alkylether compounds, by diimide reduction, using amounts of disodiumazodiformate reactant appropriate to the degree of unsaturation of thePGE, PGF-, PGA-, or PGB-type 15-alky1 ether reactant.

Example 13.-PGF IS-Methyl Ether (Formula VII: R is hydrogen, R ismethyl, and is alpha) Refer to Chart D, step g, wherein D is E is-CH=CH, R and R are methyl, V is CH=CH- (CH and W is l-pentyl. Asolution of PGF methyl ester, 15- methyl ether (Example 5B, 0.15 g.) ina mixture of methanol (4.5 ml.) and water (1.5 ml.) is cooled to 5 C.and 0.6 ml. of 45% aqueous potassium hydroxide is added. The mixture isleft standing 3.5 hrs. at about 25 0., then is diluted with 75 ml. ofwater and extracted with ethyl acetate to remove any neutral material.The aqueous layer is acidified with dilute hydrochloric acid andextracted several times with ethyl acetate. The combined ethyl acetateextracts are washed with water and brine, dried over sodium sulfate, andevaporated to give the Formula VII title compound. Mass spectral peaksat 353, 350, 336, 318, 300, 264, and 261; infrared spectral absorptionsat 3420, 2950, 2720, 2660, 1715, 1680, 1330, 1270, 1205, 1130, 1075,980, and 925 cm.-

Following the procedure of Example 13, each of the. esters of PGF15-methyl ether, described following Example B, as well as each of theesters of racemic PGF 15-methyl ether, is saponified to yield thecorresponding PGF 15-methyl ether, or racemic PGF IS-methyl ether freeacid. Likewise the esters of PGF 15-methyl ether, and racemic PGF15-methyl ether, are saponified to the corresponding free acids.

Example 14.-PGE 15-Methyl Ether (Formula III: R is hydrogen, and R ismethyl) A solution of PGFZM 15-methyl ether, (0.1 g.) in 40 ml. ofacetone is cooled to C. To it is added 110% of the theoretical amount ofJones reagent (in the proportions of 21 g. of chromic anhydride, 60 ml.of water, and 17 ml. of concentrated sulfuric acid), precooled to 0 C.,with vigorous stirring. After about 10 min., isopropyl alcohol (1 ml.)is added to the cold reaction mixture. After 5 min., the mixture isfiltered and the filtrate is concentrated under reduced pressure. Theresidue is mixed with 5 ml. of brine and the mixture is extractedseveral times with ethyl acetate. The combined ethyl acetate extractsare washed with brine, dried with anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue is subjected to silicagel chromatography, eluting with 50l00% ethyl acetate-Skellysolve B.Those fractions shown by TLC to contain the desired product are combinedand concentrated to yield the Formula HI title compound. Mass spectralpeaks at 348, 334, 330, 316, 298, and 277; infrared spectral absorptionsat 3420, 3200 (broad), 2650, 1735, 1710, 1285, 1240, 1155, 1085, 1075,and 970 cmr Following the procedure of Example 14 but replacing PGF-methy1 ether, with racemic PGF 15-methyl ether, there is obtainedracemic PGE 15-methyl ether.

Example 15 .-PGE 15-Methy1 Ether Free Acid by Enzymatic Hydrolysis(Formula II: R is hydrogen, and R is methyl) A. Enzyme preparation: Amedium is prepared consisting of 2% corn steep liquor (a mixture ofequal parts of cerelose and glucose) in tap water. This is brought to pH4.5 by adding hydrochloric acid, and 1% of methyl oleate is added. Four500 ml. flasks each containing 100 ml. of the above medium areinoculated with Cladosporium resinae (C-ll, ATCC 11,274; and are placedon a shaker at room temperature (about 28 C.) for 4 days. The culture isthen placed in 40 ml. centrifuge tubes and centrifuged at about 2000r.p.m. in a clinical centrifuge. The liquid is decanted from thecentrifuge tubes and the collected cells are washed with cold water. Thewashed cells from 2 centrifuge tubes are suspended in 50 ml. of ice cold0.05 M pH 7.0 phosphate buffer and placed in small Waring blender cupchilled with ice. Glass beads are added and the suspended cells arechurned in the blender for 15 minutes. The resulting suspension ofbroken cells is centrifuged in a clinical centrifuge at about 2000r.p.m. for 15 minutes at room temperature, then the supernatant liquidis collected. This supernatant liquid contains Cladosporium resinaeacylase and is used directly for the hydrolysis of alkyl esters or isstored, preferably frozen, until needed.

B. Esterase hydrolysis: Ten milliliters of the supernatant liquidcontaining Cladosporz'um resinae acylase, prepared as described in partA of this example and 50 mg.

of PGE 15-methyl ether, methyl ester are shaken at room temperatureunder nitrogen for about 19 hours, then 70 ml. of acetone is added andthe mixture is filtered giving a filtrate and an insoluble residue. Thefiltrate is evaporated under reduced pressure. The residue is subjectedto silica gel chromatography, eluting with 50100% ethylacetate-Skellysolve B, combining those fractions shown by TLC to containthe product free of starting material and impurities, and concentratingto the Formula II free acid product.

Following the procedure of Example 15, each of the methyl, ethyl, andother alkyl esters defined above in and after Examples 3, 5, 5A, 5B, 6,6A, 7, 8, 8A, 9, 10, 11, and 12 is hydrolyzed enzymatically to thecorresponding 15-alkyl ether PG-type free acid.

Example 16.-PGA Methyl Ether, Methyl Ester (Formula XIII: R and R aremethyl) A solution of diazomethane (about 50% excess) in diethyl etherml.) is added to a solution of 15-methyl-PGA (Example 9, 50 mg.) in 25ml. of a mixture. of methanol and ethyl ether (1:1). The mixture isallowed to stand at 25 C. for 5 min. Then, the mixture is evaporated togive the Formula XIII title compound.

Following the procedure of Example 16, each of the other specific15-alkyl ether PGE-type, PGF-type, PGA- type, and PGB-type free acidsdefined above is converted to the corresponding methyl ester.

Also following the procedure of Example 16, but using in place of thediazomethane, diazoethane, diazdbutane, 1-diazo-2-ethylhexane, anddiazocyclohexane, there are obtained the corresponding ethyl, butyl,2-ethylhexyl, and cyclohexyl esters of PGA,, methyl ether. In the samemanner, each of the other specific [5-alkyl] ether tPGE- type, PGF-type,PGA-type, and PGB-type free acids defined above is converted to thecorresponding ethyl, butyl, 2-ethylhexyl, and cyclohexyl esters.

Example 17.--PGE 15-Methyl Ether, Sodium Salt (Formula III: R; is sodiumand R is methyl) A solution of PG E 15-methyl ether (Example 3,

mg.) in 50 ml. of a water-ethanol mixture (1:1) is cooled to 5 C. andneutralized with an equivalent amount of 0.1 N aqueous sodium hydroxidesolution. The neutral solution is evaporated to give the title compound.

or a racemic compound of that formula and the mirror image thereof,wherein E is CH CH or trans CH=CH; wherein V is either (CH or cisCH=CH-(CH provided that E is CH CH only when V is (CH wherein W isl-penthyl or cis l-pent-Z-enyl provided that W is cis 1-pent-2-enyl onlywhen E is trans CH==CH-- and V is 39 wherein indicates attachment to thecyclopentane ring in alpha or beta configuration; wherein R is hydrogenalkyl of one to 8 carbon atoms, inclusive, or a pharmacologicallyacceptable cation, and wherein R is alkyl of one to carbon atoms,inclusive, with the proviso that R is not methyl when E is trans CH=CH,V is W is l-pentyl, and is alpha.

2. An optically active or racemic compound according to claim 1 whereinE is trans CH=CH-, V is (CH and W is l-pentyl.

3. An optically active or racemic compound according to claim 1 whereinE is trans --CH=CH-, V is cis CH=CH(CH and W is l-pentyl.

4. An optically active or racemic compound according to claim 1 where Eis trans -CH(=CH, V is CH=CH(CH and W is cis 1-pent-2-enyl.

5. An optically active or racemic compound according to claim 1 whereinE is CH CH V is (CH and W is l-pentyl.

6. PGF IS-methyl ether, an optically active compound according to claim2 wherein R is hydrogen, R is methyl, and indicates alpha attachment.

7. PGF IS-methyl ether, an optically active compound according to claim2 wherein R is hydrogen, R is methyl, and indicates beta attachment.

8. PGF IS-methyl ether, an optically active compound according to claim3 wherein R is hydrogen, R is methyl, and indicates beta attachment.

References Cited Bundy et al.: Prostaglandins Symposium, Sept. 17, 1970,pp. 84-85.

McComie: Advances in Organic Chemistry 3, 216- 221 (1963).

ROBERT GERSTL, Primary Examiner US. Cl. X.R.

260211 R, 247.2 R, 268 R, 293.65, 326.3, 340.2, 343.3, 345.7, 429.9, 439R, 448 R, 448.2 R, 468 D, 501.1, 501.15, 501.17, 501.2; 424305, 317

